title: Subsite specificity of anthrax lethal factor and its implications for inhibitor development.
abstract: The lethal factor of Bacillus anthracis is a major factor for lethality of anthrax infection by this bacterium. With the aid of the protective antigen, lethal factor gains excess to the cell cytosol where it manifests toxicity as a metalloprotease. For better understanding of its specificity, we have determined its residue preferences of 19 amino acids in six subsites (from P3 to P3') as relative k(cat)/K(m) values (specificity constants). These results showed that lethal factor has a broad specificity with preference toward hydrophobic residues, but not charged or branched residues. The most preferred residues in these six subsites are, from P1 to P3', Trp, Leu, Met, Tyr, Pro, and Leu. The result of residue preference was used to design new substrates with superior hydrolytic characteristics and inhibitors with high potency. For better use of the new findings for inhibitor design, we have modeled the most preferred residues in the active site of lethal factor. The observed interactions provide new insights to future inhibitor designs.
authors.affiliation: Protein Studies, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA. fengli6870@gmail.com
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Simon
authors.initials: S
authors.lastname: Terzyan
authors.forename: Jordan
authors.initials: J
authors.lastname: Tang
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D000942:Antigens, Bacterial / Q000737:chemistry*; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D015195:Drug Design; D057927:Hydrophobic and Hydrophilic Interactions; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013379:Substrate Specificity
chemical_list: D000900:Anti-Bacterial Agents; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D011480:Protease Inhibitors; C030325:anthrax toxin